ES2992643T3 - Esketamine-suspension-tts - Google Patents

Abstract

The present invention relates to a transdermal therapeutic system, comprising a support layer, which is not permeable to the active ingredient, and at least one matrix layer on one side of the support layer, wherein the matrix layer contains at least one pressure-sensitive adhesive and ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the at least one pressure-sensitive adhesive comprises a silicone pressure-sensitive adhesive, as well as to its use as a medicament, in particular for the treatment of depression and pain. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

STT comprising a suspension of esketamine

The present invention relates to a transdermal therapeutic system (TTS) comprising ketamine as an active ingredient. The invention further relates to such a system for use as a pharmaceutical, in particular for use in the treatment of depression and/or pain.

In recent years, transdermal therapeutic systems have become increasingly important as a dosage delivery method for the treatment of numerous diseases, as they offer advantages over conventional dosage forms. These are, for example, a precise and constant drug release, which is necessary for a constant concentration of the active ingredient in the blood plasma. In addition, the first-pass effect can be avoided and compliance can be increased, as the patient does not need to take tablets regularly. An advantage of transdermal therapeutic systems over other topical delivery systems, such as ointments or creams, is that they can be applied precisely to one area and therefore at a precise dose, and that there is no risk of accidental dislodgement of the ointment with contamination of other areas. In addition, ointments or tablets must be administered regularly, as a sustained release of the active ingredient cannot usually be achieved otherwise.

Document No. US 2018/064655 discloses a transdermal patch comprising (2R,6R)-hydroxynorketamine or a conjugate thereof.

Document No. EP1386604A1 discloses a transdermal delivery system (TS) comprising a backing layer inert to the matrix components, a self-adhesive matrix containing an amine-functional drug and a protective sheet or foil to be removed before use, characterized in that the self-adhesive matrix consists of a solid or semi-solid semipermeable polymer.

Through the URL: http://www.healthcare-plus.com.tw/big5/pdf/02-02.pdf, amine-compatible silicone adhesives were found on August 9, 2016.

A few years ago it was believed that the implementation of active ingredients in a transdermal therapeutic system would be easy to achieve, and that this form of application would therefore be available for a large number of active ingredients. However, this has turned out not to be true, as the molecular transport of ingredients through the skin poses a limiting factor. Thus, intensive research is always required in order to provide transdermal therapeutic systems for the delivery of new active ingredients.

The active ingredient ketamine has long been known for the treatment of pain. Recently, ketamine has also been found to be suitable for the treatment of psychological disorders, particularly depression.

A transdermal therapeutic system provides an attractive option for ketamine delivery.

Transdermal therapeutic systems for the administration of ketamine are known from the prior art.

For example, WO 2017/003935 A1 and WO 2018/195318 A1 disclose a TTS for the administration of ketamine, where a pressure-sensitive adhesive comprising free carboxy groups as well as crystallization inhibitors is used.

In known formulations using (meth)acrylate-based pressure-sensitive adhesives, ketamine is dissolved in the (meth)acrylate-based pressure-sensitive adhesives. This can be problematic because the saturation concentration of ketamine in (meth)acrylate-based pressure-sensitive adhesives is rather low. In the case where ketamine is present at higher concentrations in (meth)acrylate-based pressure-sensitive adhesives, ketamine has a tendency to recrystallize in the (meth)acrylate-based pressure-sensitive adhesives. Higher concentrations of ketamine in (meth)acrylate-based pressure-sensitive adhesives can thus usually only be achieved by the additional use of crystallization inhibitors and solubility enhancers. In all cases, ketamine has a tendency to recrystallize in (meth)acrylate-based pressure-sensitive adhesives, which negatively affects the stability of such formulations.

Furthermore, the STTs for ketamine delivery known from the prior art require optimization with respect to the flow of the active ingredient and the utilization of the active ingredient contained in the matrix layer. Furthermore, it is advantageous to provide formulations in which ketamine is present in a stable form without using crystallization inhibitors and/or solubility enhancers.

Thus, it was an object of the present invention to provide a TTS for the administration of ketamine, which exhibits an optimal, i.e. as high as possible, flux of active ingredient, especially in the first 2 to 12 hours after application, and in which the ketamine contained in the matrix layer is utilized in an optimal manner. Furthermore, the ketamine contained in the TTS will be present under conditions in which it is chemically and physically as stable as possible. Furthermore, the TTS will be simple in design and inexpensive to produce. In particular, the ketamine will be present in the TTS in an undissolved state, so that recrystallization can be avoided. Furthermore, the TTS will not comprise a crystallization inhibitor. The TTS according to the present invention will, however, exhibit a flux of ketamine which is comparable to that of known formulations based on (meth)acrylate-based pressure-sensitive adhesives.

This task has been unexpectedly solved by a transdermal therapeutic system according to claim 1.

Preferred embodiments are provided in the dependent claims.

In the present disclosure, the terms "comprising" or "containing" may also mean "consisting of."

The present invention relates to a transdermal therapeutic system comprising a backing layer, which is not permeable to the active ingredient, and at least one matrix layer on one side of the backing layer, wherein the matrix layer contains at least one pressure-sensitive adhesive and ketamine, or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pressure-sensitive adhesive or adhesives comprise a silicone pressure-sensitive adhesive and wherein the matrix layer comprises at least one penetration enhancer comprising methyl laurate.

Various types of transdermal therapeutic systems are generally known to the person skilled in the art. There are DIR (drug-in-reservoir) systems, which comprise a backing layer, a reservoir layer, an adhesive layer and optionally a removable protective layer. In these systems, the pharmaceutically active ingredient is only present in the reservoir layer, but not in the adhesive layer, which contains at least one adhesive polymer.

Furthermore, DIA (drug-in-adhesive) systems are known, in which a reservoir layer is omitted and the pharmaceutically active ingredient is present directly in the adhesive layer (also called matrix layer), which contains at least one adhesive polymer.

The advantages of DIA systems over DIR systems include, among others, a simpler production process and a lower risk of abuse. The lower risk of abuse is highly relevant, in particular with regard to the active ingredient ketamine.

Thus, the transdermal therapeutic system according to the present invention is preferably a DIA system. That is, the active ingredient, ketamine, or a pharmaceutically acceptable salt or solvate thereof, is preferably present together with at least one pressure-sensitive adhesive in a single layer.

This STT is characterised by its relatively simple design and thus by an economically advantageous production. Furthermore, this STT features a higher flow of active ingredient compared to known STTs.

It should be noted that ketamine is only soluble in the silicone pressure-sensitive adhesive in a sufficiently low concentration not exceeding 1% by weight. With such low solubility, ketamine is present in an undissolved state and therefore does not exhibit a tendency to recrystallization, which does not require any additional crystallization inhibitors and/or solubility enhancers.

The STT according to the present invention is therefore preferably a suspension STT, which implies that ketamine is present in an undissolved state in the silicone pressure-sensitive adhesive. Ketamine is preferably present in the silicone pressure-sensitive adhesive in an undissolved state in an amount of 99% or more and only dissolved in the silicone pressure-sensitive adhesive in an amount of 1% or less.

The concentration, in particular the saturation concentration, of ketamine in the silicone pressure-sensitive adhesive can be determined by the following methods.

A polymer film, partially containing the active ingredient in the form of a crystalline suspension (donor layer), is contacted with the drug-free patch matrix (acceptor layer) through a diffusion membrane.

This "sandwich" is stored and the concentration of the active ingredient in the patch matrix is determined after certain time intervals following detachment from the membrane. If it remains constant, the saturation concentration has been reached.

In this case, the donor is the silicone pressure-sensitive adhesive. The membrane is a suitable membrane and the acceptor, which will be smaller than the donor, is made of the same material as the acceptor. A smaller weight per area of the acceptor accelerates the attainment of the saturation concentration.

To measure the content and concentration of the active substance, the acceptor layer must be peeled off the membrane.

Another method to determine the concentration, in particular the saturation concentration of ketamine in silicone pressure-sensitive adhesive is as follows:

Inoculum crystals as small as possible are brought into contact with the drug-loaded polymer film and their growth and dissolution behaviour is assessed microscopically at certain intervals. Therefore, films with different concentrations of active ingredients were produced and examined microscopically for their spontaneous recrystallisation behaviour. The films can be prepared directly on a microscopy slide.

However, another method to determine the concentration, in particular the saturation concentration of ketamine in silicone pressure-sensitive adhesive is as follows:

Masses with different concentrations of active ingredients are prepared in vials and examined macroscopically for their spontaneous recrystallization behavior.

The vials are not sealed, so that the solvents can evaporate under room temperature conditions. Although all three methods described above lead to essentially the same results, the "sandwich" method is preferred.

In addition, the ketamine contained in the matrix layer can be utilized in an optimal manner.

Furthermore, the STT according to the present invention has a high skin tolerance.

The term "optimally utilized" denotes that the ketamine contained in the matrix layer diffuses from the matrix layer into the patient's skin to the maximum extent possible during application of the STT to the patient's skin, so that after application, the smallest possible amount of "unused" active ingredient remains in the matrix layer.

The expression "backing layer, which is not permeable to the active ingredient" denotes that the backing layer is essentially, preferably completely, impermeable to the active ingredient ketamine.

Suitable materials for the backing layer comprise materials such as polyesters, e.g. polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polyolefins, such as polyethylene or polypropylene, ethylene vinyl acetate, polyvinyl chloride, polyamide (nylon) and/or polyurethane. The backing layer may also be composed of a composite material and preferably comprises an aluminium-coated film and one of the materials provided above.

A pressure-sensitive adhesive preferably comprises or is a polymer, which acts as a pressure-sensitive adhesive, as defined in DIN EN 923:2016-03.

The STT according to the invention comprises ketamine as a pharmaceutically active ingredient.

Ketamine is (S)-(+)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one ((S)-ketamine), (R)-(-)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one ((R)-ketamine), as well as the racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one. Also included are pharmaceutically acceptable salts and solvates of said compounds. Additionally included are mixtures of said compounds.

In the transdermal therapeutic system according to the present invention, ketamine is preferably present in the form of (S)-ketamine and/or a pharmaceutically acceptable salt thereof, such as (S)-ketamine HCl.

Most preferably, the pharmaceutically active ingredient in the transdermal therapeutic system according to the present invention comprises (S)-ketamine, which is present in the form of the free base of ketamine.

In certain embodiments, the STT may comprise any additional pharmaceutically active ingredient other than ketamine, which may be, for example, one or more of the group of nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, ketoprofen, meloxicam, piroxicam, or indomethacin), COX-2 inhibitors (e.g., celecoxib or etoricoxib), opioids (e.g., fentanyl, buprenorphine, morphine, codeine, oxycodone, hydrocodone, dihydromorphine, or pethidine), MAOIs (irreversible and nonselective, e.g., phenelzine, tranylcypromia, and isocarboxazid), MAOIs (reversible MAO-A inhibitors, e.g., moclobemide), MAOIs (preferential MAO-B inhibitor, e.g., deprenyl), tricyclic antidepressants (and tetracyclic) (e.g., clomipramine, imipramine, amitriptyline, nortriptyline, protriptyline, maprotiline, amoxapine, doxepin, desipramine, or trimipramine), selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, or escitalopram), selective norepinephrine reuptake inhibitors (e.g., e.g., reboxetine or atomoxetine), norepinephrine and dopamine reuptake inhibitors/releasers (e.g., bupropion), serotonin and norepinephrine reuptake inhibitors (e.g., venlafaxine, milnacipran, or duloxetine), serotonin antagonists/reuptake inhibitors (e.g., nefazodone or trazodone), and alpha2-adrenoceptor antagonists (e.g., mirtazapine).

Preferably, the silicone pressure-sensitive adhesives are obtained after a condensation reaction between a silane-terminated polydimethylsiloxane (PDMS) and a silicate, preferably a silicate resin. The silicone pressure-sensitive adhesives are preferably further reacted with trimethylsilyl in order to reduce the silanol content of the adhesive polymer. The silicone pressure-sensitive adhesives are then preferably diluted in the appropriate solvent, e.g. n-heptane, in order to obtain solvent-based silicone pressure-sensitive adhesives.

In principle, the solvent is not limited. However, it is preferred to use a solvent in which ketamine is not soluble or is only slightly soluble. Preferably, ketamine is only soluble in the solvent in an amount of less than 3% by weight, preferably less than 2% by weight, and most preferably less than 1% by weight.

Most preferably, the solvent comprises n-heptane or is n-heptane.

Preferably, the silicone pressure-sensitive adhesives which can be used according to the present invention are pressure-sensitive adhesives produced on the basis of silicone polymers, such as dimethiconol/trimethylsiloxysilicate crosspolymer and/or a trimethylsilyl-treated dimethiconol/trimethylsiloxysilicate crosspolymer, which preferably contains at least 30% by weight, in particular between 35% and 95% by weight, particularly preferably between 40% and 90% by weight or between 40% and 60% by weight or between 45% and 55% by weight of one or more silicone polymers based on the silicate.

In one embodiment, the silicone pressure-sensitive adhesives that can be used according to the present invention are pressure-sensitive adhesives produced on the basis of silicone polymers, such as dimethiconol/trimethylsiloxysilicate crosspolymers and/or trimethylsilyl-treated dimethiconol/trimethylsiloxysilicate crosspolymers, preferably containing 40% by weight of silicone polymers and 60% by weight of silicate. Such adhesives may be referred to as "intermediate tack adhesives".

In another embodiment, the silicone pressure-sensitive adhesives that can be used according to the present invention are pressure-sensitive adhesives produced on the basis of silicone polymers, such as dimethiconol/trimethylsiloxysilicate crosspolymers and/or trimethylsilyl-treated dimethiconol/trimethylsiloxysilicate crosspolymers, preferably containing 45% by weight of silicone polymers and 55% by weight of silicate. Such adhesives may be referred to as "high tack adhesives".

Preferably, the STT according to the present invention comprises a 1:1 ratio (by weight) of an "intermediate tack adhesive" and a "high tack adhesive", as described above.

The advantage of such a mixture is that the so-called "cold flow" can be minimized. "Cold flow" is understood as the leakage of adhesive outwards from the edges of the STT, especially during storage.

All silicone pressure sensitive adhesives such as those described above preferably contain n-heptane as solvent.

Silicone pressure-sensitive adhesives such as those described above are preferably present in an amount of between 50% and 80% by weight, preferably between about 60% and 75% by weight of solids content in the respective solvent, preferably in n-heptane.

Preferably, the silicone pressure sensitive adhesives have a peel adhesion of approximately 700 g/cm for the high tack adhesive and/or 900 g/cm for the intermediate tack adhesive, as defined above.

Preferably, the silicone pressure sensitive adhesives have a shear value of about 14 kg/6.3 cm3 for the high tack adhesive and about 17 kg/6.3 cm3 for the intermediate tack adhesive, as defined above.

Preferably, the pressure sensitive adhesives have a viscosity at 0.01 rad/s and 30 °C (mPas) of about 5x108 mPas (5x106 P) for the high tack adhesive and about 1*101° mPas (1x108 P) for the intermediate tack adhesives, as defined above.

The use of such silicone pressure-sensitive adhesives, preferably if they are based on n-heptane, is because ketamine is not soluble in these substances.

In a preferred embodiment, the transdermal therapeutic system according to the present invention comprises as the pressure-sensitive adhesive at least one of the above-mentioned silicone pressure-sensitive adhesives, which further preferably contains a silicone polymer formed from polydimethyldiphenyl siloxane.

Silicone pressure sensitive adhesives for use in the present invention may additionally contain oils and/or other softeners (plasticizers).

Furthermore, mixtures or condensates of silicone resins and polyorganosiloxanes are also considered. Amine-resistant silicone pressure-sensitive adhesives are also preferred, which are characterized by the fact that they contain no or only few free silanol functions, since the Si-OH groups are alkylated.

In a preferred embodiment, a silicone pressure-sensitive adhesive is used which softens upon heating and thus reaches a viscosity which is suitable for incorporating one, two or more drugs in solid form, as well as for application by extrusion or slot coating, which, after cooling, is again present in a non-fluid state.

The softening temperature of suitable silicone pressure-sensitive adhesives is in the range of 50 °C to 200 °C, preferably 75 °C to 170 °C, and particularly preferably 100 °C to 150 °C.

Silicone pressure sensitive adhesives suitable for use in the present invention are, for example, the hot melt pressure sensitive adhesives BIO-PSA Q7-4201 and/or BIO-PSA 4301 from Dow Corning. Thus, BIO-PSA Q7-4201 is an "intermediate tack adhesive" and BIO-PSA Q7-4301 is a "high tack adhesive" as defined above. Silicone pressure sensitive adhesives and in particular silicone hot melt pressure sensitive adhesives suitable for use in the present invention and as described above are known to those skilled in the art and are commercially available.

Furthermore, the transdermal therapeutic system according to the present invention is preferably characterized in that at least one silicone pressure-sensitive adhesive is present in the matrix layer in an amount of between 70% and 95% by weight, preferably between 75% and 95% by weight, more preferably between 78% and 92% by weight, relative to the total weight of the matrix layer.

Furthermore, the transdermal therapeutic system according to the present invention is preferably characterized in that the matrix layer does not comprise any pressure-sensitive adhesive comprising (meth)acrylate groups. This has the advantage that ketamine is present in the TTS in an undissolved state. In this way, recrystallization is avoided.

In particular, the matrix layer shall not comprise any pressure-sensitive adhesive comprising an acrylic copolymer selected from 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate comprising free hydroxyl groups. Pressure-sensitive adhesives which should be avoided in the matrix layer are known under the trade name DURO-TAK, in particular DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 2287 or DURO-TAK 2510 from Henkel, Germany.

Penetration enhancer(s) are compounds that stabilize the active ingredients and thus provide a relatively high and long-term resorption of the active ingredient through the skin.

In another embodiment, at least one additional penetration enhancer is selected from carboxylic acids, fatty acids and/or fatty acid esters, such as levulinic acid, valeric acid, hexanoic acid, caprylic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutanoic acid, neoheptanoic acid, neonanonic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, vaccenic acid, petroselinic acid, elaidic acid, arachidonic acid, gadoleic acid, erucic acid, methyl propionate, methyl valerate, diethyl sebacate, ethyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate, propyl palmitate, propylene glycol ... of isopropyl and/or isopropyl oleate.

In another embodiment, the STT according to the present invention does not comprise levulinic acid.

Furthermore, compounds such as diethyltoluamide (DEET), propylene glycol monocaprylate, propylene glycol, polyethylene glycol, diisopropyl adipate, eugenol, transcutol, lauryl lactate and/or oleyl alcohol are suitable as penetration enhancers.

The transdermal therapeutic system according to the present invention is characterized in that at least one penetration enhancer comprises methyl laurate, because methyl laurate has the advantage that ketamine shows a rapid onset of transdermal flow.

The transdermal therapeutic system according to the present invention is more preferably characterized in that only one penetration enhancer, only methyl laurate, is present in the matrix layer or layers.

Furthermore, the transdermal therapeutic system according to the present invention is preferably characterized by the presence of at least one penetration enhancer in the matrix layer in an amount of between 1% and 15% by weight, preferably between 2% and 12% by weight, most preferably about 10%, based on the weight of the matrix layer.

It is preferred that the transdermal therapeutic system according to the present invention contains ketamine in the matrix layer in an amount of between 1% and 25% by weight, preferably between 5% and 15% by weight, based on the weight of the matrix layer.

The transdermal therapeutic system according to the present invention is further preferably characterized in that the matrix layer comprises at least one antioxidant.

Antioxidant(s) are a chemical compound that prevents or reduces the oxidation of other substances, in particular of the active ingredient, and thus acts against the ageing of the therapeutic system. In particular, antioxidants are characterised by their effect as radical scavengers and by preventing the oxidative decomposition of sensitive molecules, in particular of the active ingredient, caused by oxygen in the air. The antioxidant(s) are preferably selected from the group consisting of alpha-tocopherol, ascorbyl palmitate and/or dibutylhydroxytoluene.

Preferably, the transdermal therapeutic system according to the present invention contains at least one antioxidant in the matrix layer in an amount of between 0.001% and 5% by weight, preferably between 0.01% and 2% by weight, relative to the entire weight of the matrix layer.

In addition to the above-mentioned components, the matrix layer may also comprise customary additives. Depending on their function, these can be classified as softeners/plasticizers, tackifiers, carriers and/or fillers. The relevant, physiologically non-critical substances are known to those skilled in the art.

Carriers and/or fillers, such as silica gels, titanium dioxide and zinc oxide, can be used together with the polymer in order to influence certain physical parameters, such as cohesion and adhesion strength, in a desired manner.

In addition, abuse-deterrent agents may be added to the transdermal therapeutic system to prevent, or at least reduce, its abuse potential. Examples of substances that may be used as abuse-deterrent agents are bittering agents, gelling agents, irritants, substances that lead to acute gastrointestinal, cardiac or respiratory effects; substances that lead to violent nausea or vomiting; substances that lead to offensive odours; sleep-inducing substances; substances that lead to deactivation or degradation of the active ingredient in the event of attempted extraction.

Furthermore, the transdermal therapeutic system may further comprise an abuse-deterrent feature that renders the active ingredient and/or system ineffective when used in any manner other than its intended use, i.e., transdermal application.

Preferably, the transdermal therapeutic system according to the present invention is further characterized in that the matrix layer has a surface weight of between 30 and 400 g/m2, preferably between 50 and 250 g/m2, most preferably between 70 and 150 g/m2.

Preferably, the transdermal therapeutic system according to the present invention is further characterized in that the transdermal therapeutic system comprises a removable protective layer on the side of the matrix layer on which the backing layer is not provided.

The removable protective layer, which is in contact with the matrix and is removed before application, comprises, for example, the same materials as those used for the production of the backing layer, provided that they are made removable, e.g. by silicone treatment. Other removable protective layers are polytetrafluoroethylene, treated paper, cellophane, polyvinyl chloride and the like.

Furthermore, the present invention relates to a transdermal therapeutic system as described above for use as a medicament.

The present invention further relates to a transdermal therapeutic system as described above for use in the treatment of major depressive disorder (MDD) (also known simply as "depression"). In particular, the transdermal therapeutic system can be used for suicide risk reduction and/or for the treatment of treatment-resistant depression (TRD).

Major depressive disorder (MDD) is a mental disorder characterized by persistent, pervasive low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Major depressive disorder is a disabling condition that negatively affects a person's family, work, or school life, sleep and eating habits, and general health.

Treatment-resistant depression (TRD) describes a condition affecting people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain period of time.

Additional subtypes, recognized by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5), include melancholic depression, atypical depression, catatonic depression, depression with anxious distress, peripartum-onset depression, and seasonal affective disorder.

The present invention further relates to a transdermal therapeutic system as described above for use in the treatment of pain.

Pain is a distressing sensation often caused by intense or harmful stimuli. Pain that lasts a long time is called "chronic" or "persistent," and pain that resolves quickly is called "acute."

Nociceptive pain is caused by stimulation of sensory nerve fibers that respond to stimuli approaching or exceeding noxious intensity (nociceptors) and can be classified according to the mode of noxious stimulation. The most common categories are thermal, mechanical, and chemical. Some nociceptors respond to more than one of these modalities and are therefore referred to as "polymodal."

Nociceptive pain can also be divided into "visceral", "deep somatic", and "superficial somatic" pain.

Neuropathic pain is caused by damage or disease affecting any part of the nervous system involved in bodily sensations (the somatosensory system). Neuropathic pain can be divided into peripheral, central, or mixed (peripheral and central) neuropathic pain. Peripheral neuropathic pain is often described as a "burning," "tingling," "electrical," "stabbing," or "cramping" sensation.

Furthermore, the transdermal therapeutic system of the present invention can be used in different administration schedules, for example, in consecutive, repeated or staggered administration.

In consecutive administration, the transdermal system is applied at intervals lasting at least 12 h to achieve concentrations of active ingredient in the individual's blood plasma.

Repeated administration is preferably carried out consecutively without delays, i.e. when the STT(s) according to the present invention are removed at the end of one application interval, the STT(s) according to the present invention are immediately applied for the next application interval. Preferably, the time interval in which there could be no STT(s) according to the present invention at all applied to the body is not more than 10 minutes, more preferably not more than 5 minutes.

In a staggered administration, the transdermal system is applied at intervals lasting at least 4 h to achieve concentrations of active ingredient in the subject's blood plasma.

Staggered administration is preferably carried out once daily, twice weekly or once weekly, i.e. when the STT(s) according to the present invention are withdrawn at the end of an application interval, the STT(s) according to the present invention are immediately applied for the next application interval considering a dose-free interval of at least 18 hours.

The intended application time for the transdermal therapeutic system according to the present invention is preferably at least 6 hours, more preferably at least 12 hours, and even more preferably at least 24 hours. The amount of active ingredient is preferably adapted to the desired application time.

In a preferred embodiment, all of the STTs according to the present invention are administered to the same area of skin of the individual over a total period, i.e. a given surface of skin of the individual is covered or receives repeated application of the STTs according to the present invention.

In another preferred embodiment, all of the STTs according to the present invention are administered each time to different areas of the individual's skin over a total period, i.e. a given surface of the individual's skin is not covered or receives repeated application of the STTs according to the present invention.

The present invention will be described in greater detail below using non-limiting examples.

Examples

The following ingredients were used in the following examples.

BIO-PSA Q7-4201 and BIO-PSA 4301: dimethiconol/trimethylsiloxysilicate crosspolymer treated with trimethylsilyl. DURO-TAK 387-4287: pressure-sensitive adhesive based on an acrylate-vinyl acetate copolymer comprising free hydroxyl groups, obtained without using a crosslinking agent.

DURO-TAK 387-2054: pressure-sensitive adhesive based on a vinyl acrylate-acetate copolymer comprising free carboxyl groups, obtained by using a crosslinking agent.

Plastoid B: copolymer of butyl methacrylate and methyl methacrylate (crystallization inhibitor).

Transcutol: diethylene glycol monoethyl ether (potentiator).

Eutanol HD: 9-octadecen-1-ol (enhancer)

HPC/Isopropanol: hydroxypropylcellulose dissolved in isopropanol (gelling agent: solids content: 2% by weight).

HPC/1,2-Propanediol: hydroxypropylcellulose dissolved in 1,2-propanediol (gelling agent: solids content: 2% by weight).

Crospovidone: cross-linked polyvinylpolypyrrolidone (structuring agent)

Example 1:

The formulations of the coating compositions containing S-ketamine of the present example are summarized in Table 1 below.

Table 1

* Example not according to the invention.

For Example 2a, a beaker was charged with S-ketamine base, the solvent (ethyl acetate), levulinic acid and methyl laurate. The acrylic pressure-sensitive adhesive polymer DURO-TAK 387-4287 was added and the mixture was then stirred at a speed of up to 300 rpm until a homogeneous mixture was obtained (stirring time approx. 90 min).

For Example 1b, a beaker was charged with S-ketamine base, the solvent (n-heptane) and methyl laurate. The mixture was stirred for approximately 30 min at 300 rpm and then DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 silicone pressure-sensitive adhesives were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time: approximately 90 min).

For Example 1c, a beaker was charged with the HPC/isopropanol solution, methyl laurate and S-ketamine base. The mixture was stirred for approximately 30 min at 300 rpm and then DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 silicone pressure-sensitive adhesives were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time: approximately 90 min).

For Example 1d, a beaker was charged with the HPC/1,2-propanediol solution, methyl laurate and S-ketamine base. The mixture was stirred for approximately 30 min at 300 rpm and then DOW CORNING BIO-PSA Q7-4201 and D<o>W<CORNING BIO-PSA Q7-4301 silicone pressure sensitive adhesives were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time: approximately 90 min).

For Example 1e, a beaker was charged with S-ketamine base, the solvent (ethyl acetate), levulinic acid, Eutanol h>D< and Transcutol. DURO-TAK 387-2054 acrylic pressure sensitive adhesive polymer was added and the mixture was then stirred at up to 300 rpm for approximately 30 min. Plastoid B was added and the mixture was then stirred at up to 350 rpm until a homogeneous mixture was obtained (stirring time approximately 120 min).

For Example 1f, a beaker was charged with the HPC/1,2-propanediol solution and S-ketamine base. The mixture was stirred for approximately 30 min at 300 rpm and then DOW CORNING BIO-PSA Q7-4201 and DOW CORNING BIO-PSA Q7-4301 silicone pressure-sensitive adhesives were added. The mixture was then stirred at up to 900 rpm until a homogeneous mixture was obtained (stirring time: approximately 90 min).

For Examples 1a and 1e, the resulting S-ketamine-containing coating composition was used to coat a polyethylene terephthalate film (silicone-coated, 75 µm thick, capable of acting as a release liner) and dried for ca. 15 min at room temperature and for 15 min at 60 °C. The coating thickness gave a matrix layer area weight of 78.9 g/m2 (Example 1a) and 81.5 g/m2 (Example 1e), respectively. The dried film was laminated to a polyethylene terephthalate backing layer (23 µm thick), providing a self-adhesive layer structure containing S-ketamine.

For Examples 1b, 1c, 1d and 1f, the resulting S-ketamine-containing coating composition was used to coat a polyethylene terephthalate film (fluoropolymerized, 75 µm thick, capable of acting as a release liner) and dried for ca. 15 min at room temperature and for 15 min at 60 °C. The coating thickness gave a matrix layer area weight of 71.0 g/m2 (Example 1b), 81.9 g/m2 (Example 1c), 78.5 g/m2 (Example 1d) and 79.6 g/m2 (Example 1f), respectively. The dried film was laminated to a polyethylene terephthalate backing layer (19 µm thick), providing a self-adhesive layer structure containing S-ketamine.

The individual systems were then die-cut from the self-adhesive layer structure containing S-ketamine. In specific embodiments, an STT as described above may be provided with an additional self-adhesive layer of larger surface area, preferably with rounded corners, comprising a matrix layer with pressure-sensitive adhesive which is free of active agent. This is advantageous when the STT, based on its physical properties alone, does not sufficiently adhere to the skin and/or in case the matrix layer containing S-ketamine, in order to avoid generation of waste, has sharp corners (square or rectangular shapes). The systems are then die-cut and sealed in bags of the primary packaging material.

Measurement of skin permeation rate

The permeated amount and the corresponding skin permeation rates of the STT prepared according to Examples 1a-1f were determined by in vitro experiments in accordance with OECD guidelines (adopted on 13 April 2004) and EMA guideline on the quality of transdermal patches (EMA/CHMP/QWP/608924/2014, adopted on 23 October 2014), performed using a 7.0 ml Franz diffusion cell. Split-thickness human abdominal skin (female) was used. A dermatome was used to prepare skin at a thickness of 500 µm, with an intact epidermis for all STTs. Punches with an area of 1.152 cm2 were punched from the STT. The amount of S-ketamine permeated into the receiving medium of Franz cell (phosphate buffer solution, pH 5.5, with 0.1% azide saline as an antibacterial agent) at a temperature of 32±1 °C after 72 h, and the corresponding skin permeation rate [pg/cm2*h] was calculated. The results are shown in Table 2 and Figure 1.

Table 2

Use of S-ketamine

S-ketamine utilization at 72 h was calculated based on the amount of S-ketamine permeated into the recipient and the initial S-ketamine content in the TTS. The results are shown in Table 3 and Figure 2.

Table 3:

The results summarized in Figs. 1 to 2 show improved utilization of the active ingredient and improved flow of active ingredient compared to a formulation with an acrylic adhesive.

Example 2:

The formulations of the coating compositions containing S-ketamine of Examples 2a-d were prepared analogously as described in Example 1 and summarized in Table 4 below.

Table 4:

The skin permeation rate was determined analogously to Example 1 and is summarized in Figure 3.

Use of S-ketamine

S-ketamine utilization at 72 h was calculated based on the amount of S-ketamine permeated into the recipient and the initial S-ketamine content in the TTS. The results are shown in Table 5 and Figure 4.

Table 5:

The results summarized in Figs. 3 to 4 show improved utilization of the active ingredient by reducing the coating weight and faster onset and higher flow by using a higher concentration of enhancer. Crospovidone is an equivalent alternative compared to HPC. Example 3:

The formulations of the coating compositions containing S-ketamine of Examples 3a-h (not according to the invention) were prepared analogously as described in Example 1 and summarized in Table 6 below.

Table 6:

The skin permeation rate and utilization of (S)-ketamine were analyzed analogously to Example 1.

The corresponding results are provided in Figures 5 and 6, respectively.

Claims (14)

i. A transdermal therapeutic system, comprising a backing layer, which is not permeable to the active ingredient, and at least one matrix layer on one side of the backing layer, wherein the matrix layer contains at least one pressure-sensitive adhesive and ketamine, or a pharmaceutically acceptable salt or solvate thereof, characterized in that the pressure-sensitive adhesive(s) comprise a silicone pressure-sensitive adhesive and wherein the matrix layer comprises at least one penetration enhancer comprising methyl laurate. 2. Transdermal therapeutic system according to claim 1, characterized in that the ketamine is (S)-ketamine or a pharmaceutically acceptable salt or solvate thereof. 3. Transdermal therapeutic system according to any of the preceding claims, characterized in that ketamine, preferably (S)-ketamine, is present in the form of ketamine free base. 4. Transdermal therapeutic system according to any of the preceding claims, characterized in that the silicone pressure sensitive adhesive comprises a dimethiconol/trimethylsiloxysilicate crosspolymer and/or a trimethylsilyl treated dimethiconol/trimethylsiloxysilicate crosspolymer. 5. Transdermal therapeutic system according to any of the preceding claims, characterized in that the silicone pressure-sensitive adhesive is present in the matrix layer in an amount of between 70% and 95% by weight, relative to the total weight of the matrix layer. 6. Transdermal therapeutic system according to any of the preceding claims, characterized in that it comprises an additional penetration enhancer, which is selected from levulinic acid, valeric acid, hexanoic acid, caprylic acid, nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, 3-methylbutanoic acid, neoheptanoic acid, neonanonic acid, isostearic acid, oleic acid, palmitoleic acid, linolenic acid, vaccenic acid, petroselinic acid, elaidic acid, arachidonic acid, gadoleic acid, erucic acid, methyl propionate, methyl valerate, diethyl sebacate, ethyl laurate, ethyl oleate, isopropyl decanoate, isopropyl myristate, isopropyl palmitate, isopropyl oleate, diethyltoluamide, propylene glycol monocaprylate, propylene glycol, polyethylene glycol, diisopropyl adipate, eugenol, diethylene glycol monoethyl ether, lauryl lactate and/or oleyl alcohol. 7. Transdermal therapeutic system according to any of the preceding claims, characterized in that the matrix layer comprises the penetration enhancer or enhancers in an amount of between 1% and 15% by weight, relative to the total weight of the matrix layer. 8. Transdermal therapeutic system according to any of the preceding claims, characterized in that the matrix layer does not comprise any pressure-sensitive adhesive comprising (meth)acrylate groups. 9. Transdermal therapeutic system according to any of the preceding claims, characterized in that the matrix layer comprises ketamine in an amount between 1% and 25% by weight, relative to the total weight of the matrix layer. 10. Transdermal therapeutic system according to any of the preceding claims, characterized in that the matrix layer comprises at least one antioxidant, preferably selected from the group consisting of alpha-tocopherol, ascorbyl palmitate and/or dibutylhydroxytoluene. 11. Transdermal therapeutic system according to any of the preceding claims, characterized in that the matrix layer has a surface weight of between 30 and 400 g/m2. 12. Transdermal therapeutic system according to any of the preceding claims, characterized in that the transdermal therapeutic system comprises a removable protective layer on the side of the matrix layer on which the backing layer is not provided. 13. Transdermal therapeutic system according to any of the preceding claims, for use as a medicament. 14. Transdermal therapeutic system according to any of the preceding claims, for use in the treatment of depression and/or pain.